Re-emergence of herpes simplex virus type-1 and type-2 manifestations in type 2 diabetes patients: its current status, genomic characteristics, diagnosis, treatment, and future outlook
Authors: Shopnil Akash, Md. A. K. Azad, Nobendu Mukerjee, Shabana Bibi
Journal: International Journal of Surgery (2023)

The infection caused by the herpes simplex virus (HSV) type-1 (HSV-1) and type-2 (HSV-2), more often referred to as herpes, is widespread worldwide. There is no treatment for herpes that is effective in the long term at this time. HSV-1 and HSV-2 are the two kinds that are documented to produce various symptoms, which may range from acute to chronic forms of the condition. The HSV is very infectious and may be passed from person to person via any physical contact1. In addition to this, viral shedding may also occur in the absence of any symptoms caused by an infection. It produces the disease in or around the mouth (oral herpes), but it also has the capability to generate genital herpes. It represents the Alphaherpesviridae subfamily of viruses with eight different variants of HSVs identified, including HSV-1 and HSV-2, varicella-zoster virus, cytomegalovirus (CMV), Epstein–Barr virus, and human herpesviruses-6, 7 and 8. The structure of this pathogenic virus is made up of linear double-stranded DNA, an icosahedral capsid range between 100 and 110 nm in diameter, and a spikey envelope. In principle, the pathophysiology of HSV infection is thought to resemble a cycle consisting of early diseases of epithelial cells, incubation mostly in the human neurons, and resurrection of the infection. Vesicular eruptions, most often observed in the orolabial and vaginal mucosa, are caused by HSV. HSV is also accountable for chronic and reoccurring vesicular eruptions, and infection can manifest itself in a wide variety of ways, such as orolabial herpes, herpetic sycosis (HSV folliculitis), herpes gladiatorum, herpetic whitlow, ocular HSV infection, and herpes encephalitis2. In addition, type 2 diabetes affects a large number of people and has a high prevalence rate globally. Obesity and advancing age are two of the most significant risk factors for developing type 2 diabetes. Now, new research reveals HSV-2 could contribute to the development of type 2 diabetes3. More than 1200 healthy people were asked to participate in the researchers' most recent trial, which required them to have regular blood sugar levels. The participants were screened through the eight herpes viruses, including HSVs 1 and 2 (HSV-1 and HSV-2, which cause cold sores and genital herpes, respectively), varicella-zoster virus (chickenpox and shingles), the Epstein–Barr virus, and CMV. None of the participants tested positive for any of the herpes viruses. CMV was quite prevalent, as shown by the fact that 46% of participants tested positive for antibodies, a sign of a previous infection. Furthermore, just 11% of individuals tested positive for HSV-2. The majority of individuals tested positive for antibodies against many types of herpes viruses. After 7 years, 364 of the research participants acquired prediabetes. Those individuals who tested positive for HSV-2 at the beginning of the trial were 59% more likely to develop prediabetes or diabetes than those people who did not show evidence of past herpes infection. According to research published in Diabetology, those infected with CMV had a 33% increased risk of developing hyperglycemia or diabetes. The scientists could not uncover any evidence of a connection between type 2 diabetes and the HSVs4. Although this pathogenic virus was discovered more than 2000 years ago, it recently infected many people, and many more have died due to this pathogen5. In 2016, more than 13% of the world's people between the ages of 15 and 49, or about 491 million people, were thought to be living with a HSV-2 disease6. The genome of HSV-1 is a double-stranded, linear DNA molecule about 152 Kb pairs in length. Nicks and gaps are present in the replicating DNA as well as the viral genomes that have been encapsulated. These gaps are scattered around in a random pattern, and they are found on both strands. In DNA that was recovered from viruses, the number of gaps per genome was found to range from 3 to 13. It is not well understood how nicks and gaps come into existence, but it is hoped that research on nicks and gaps in the HSV genome could reveal light on how hosts react to invading viral genomes and the process by which HSV-1 replicates itself7. Again, the genome of HSV-2 is a linear, double-stranded DNA structure with an estimated length of 154,700 base pairs and a percentage of guanine–cytosine that is 69%. There have been identified at least 84 distinct open reading frames for coding proteins, in addition to other RNA transcripts that have not been shown to encode proteins. The HSV-2 genome is made up of two components that are covalently bonded to one another. These components are the unique long and unique short segments. These segments are surrounded by inverted repeat long and inverse repetition shorter regions. Because they are found within the inverted repeat long and inverse repetition shorter sequences, the five genes in question are considered to be diploid. Identification of the molecular structure and evolution of HSV-2 has been hampered for a long time by the genome's vast size and high guanine–cytosine content8. Many recent improvements have been made to the diagnostic procedures for HSV infections. These improvements include novel viral identification approaches and serological assays. The clinical diagnosis of genital herpes would generally be validated by analytical testing, including serotyping, since the serotype impacts the prognosis and the counseling. To make a conclusive diagnostic of genital herpes, it is necessary to demonstrate the presence of HSV in the genital region. This may be accomplished by the isolation of the virus or through the identification of the antigen. The determination of HSV DNA using molecular diagnostic methods gradually displaces antigen identification and viral culture in certain research facilities. When conventional approaches have negative findings, serological testing may be helpful in symptomatic patients. It can also be beneficial in asymptomatic people to detect whether or not they have had an infection in the past or now. The type of test will determine the usefulness of any laboratory test for diagnosing HSV infection, the quality of the specimen obtained, the laboratory's capacity to perform the test accurately, and the clinician's interpretation of the test results9. Acyclovir, valacyclovir, and famciclovir are antiviral medications that may be used to treat HSV infections. The molecules of these nucleoside derivatives block viral DNA polymerase, disrupting the DNA synthesis process caused by viruses. Acyclovir has the highest level of in-vitro activity against HSV-1 and HSV-2 compared to all other human herpesviruses. On the other hand, famciclovir and valacyclovir have a higher oral bioavailability than acyclovir and therefore need fewer dosages. Oral medicines usually are relatively well tolerated; nevertheless, some people may have adverse effects related to their gastrointestinal system or headaches. Because these antiviral drugs are selectively transformed into active chemicals only inside the cells that are infected with viruses, the margin of safety and tolerability that these oral medications provide is excellent. Since acyclovir and its analogs rely on renal function for clearance, a change in dosage is required in patients with moderate to severe renal insufficiency while using any of these medications10. In conclusion, it could be summarized that the HSV is very widespread in people and has the potential to enter the brain even in the absence of any obvious clinical signs. The virus will remain latent in the neural tissue for the rest of the patient's life. Once the virus has entered the central nervous system, it can either enter a dormant, latent state in this tissue or eventually actively lead to severe acute necrotizing encephalitis. This condition is characterized by exacerbated neuroinflammation and prolonged neuroimmune activation, producing a potentially fatal disease. Although antiviral drugs that limit virus replication can be used to treat HSV-1 encephalitis, neurological sequelae are common. In addition, that shows the relationship between viruses and (pre)diabetes, as well as the need for more studies assessing public health viral preventive techniques, perhaps incorporating the discovery of efficient vaccinations against herpes viruses11. Ethics approval Not applicable. Sources of funding Not applicable. Author contribution S.A. and M.A.K.A.: conceptualization; S.A., M.A.K.A., and S.B.: writing and original draft preparation; S.B. and N.M.: writing and editing; S.B.: supervision. All authors have reviewed and approved the final version of the manuscript prior to submission. Conflicts of interest disclosure The authors declare no conflicts of interest, financial or otherwise. Research registration unique identifying number (UIN) 1. Name of the registry: not required. 2. Unique identifying number or registration ID: not required. 3. Hyperlink to your specific registration (must be publicly accessible and will be checked): not required. Guarantor I, Shopnil Akash (corresponding author), take full responsibility for the work and/or the conduct of the study, had access to the data, and controlled the decision to publish. Data availability All data used to support the findings of this study are included in the article.